Antibiotics, the most effective tools against pathogens, are overused in neonatal intensive care units (NICUs). Prolonged and unnecessary empirical use of broad-spectrum antibiotics selects resistant bacteria and increases the risk of sever fungal infections. Judicious use of antibiotics and development of appropriate intervention strategies and policies in order to reduce antibiotic use should be a primary objective in all NICUs. The choice of the best empirical antibiotic regiment should be base on the age of the infant, on the clinical signs and on the pharmacokinetics of the drug, but the narrowest spectrum antibiotics should be used.